5‐HT4 receptors located on cholinergic nerves in human colon circular muscle

5‐Hydroxytryptamine 4 (5‐HT4) receptor agonists promote colonic propulsion. The alteration of circular muscle (CM) motility underlying this involves inhibition of contractility via smooth muscle 5‐HT4 receptors and proximal colonic motility stimulation, the mechanism of the latter not having been characterized. Our aim was to identify and characterize a 5‐HT4 receptor‐mediated stimulation of human colon CM contractile activity. 5‐HT4 receptor ligands were tested on electrical field stimulation (EFS)‐induced contractions of human colonic muscle strips cut in the circular direction (called ‘whole tissue’ strips). Additionally, after incubation of tissues with [3H]‐choline these compounds were tested on EFS‐induced release of tritium in whole tissue strips and in ‘isolated’ CM strips, obtained by superficial cutting in the CM layer. Tetrodotoxin and atropine blocked EFS‐induced contractions of whole tissue CM strips. Prucalopride (0.3 μmol L−1) evoked a heterogenous response on EFS‐induced contraction, ranging from inhibition (most frequently observed) to enhancement. In the release experiments, EFS‐induced tritium efflux was blocked by tetrodotoxin. Prucalopride increased EFS‐induced tritium and [3H]‐acetylcholine efflux in whole tissue and in isolated CM strips. All effects of prucalopride were antagonized by the selective 5‐HT4 receptor antagonist GR113808. The results obtained indicate the presence of excitatory 5‐HT4 receptors on cholinergic nerves within the CM of human colon.